rs186784974

chr18-45901140-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020964.3(EPG5):c.4502G>A(p.Arg1501Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,614,068 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1501W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.451

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003628403).
• BP6: Variant 18-45901140-C-T is Benign according to our data. Variant chr18-45901140-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 466250.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-45901140-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.4502G>A	p.Arg1501Gln	missense_variant	26/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.4502G>A	p.Arg1501Gln	missense_variant	26/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000795 AC: 198 AN: 248928 Hom.: 1 AF XY: 0.000851 AC XY: 115 AN XY: 135062

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1461794 Hom.: 2 Cov.: 31 AF XY: 0.000700 AC XY: 509 AN XY: 727200

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74460

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00101 Hom.: 2

Bravo AF: 0.000990

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000967 AC: 8

ExAC AF: 0.000703 AC: 85

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vici syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Benign	0.0046	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.79	N;N
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.46	N;.
REVEL	Benign	0.11
Sift	Benign	0.40	T;.
Sift4G	Benign	0.33	T;.
Polyphen		0.0010	B;B
Vest4		0.090
MVP		0.076
MPC		0.17
ClinPred		0.013	T
GERP RS		-5.8
Varity_R		0.021
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs186784974; hg19: chr18-43481105; COSMIC: COSV99957063;